The role of low frequency platelet-specific antigens as triggers for neonatal alloimmune thrombocytopenia (NATP) will be characterized more fully. Improved methods for detecting and identifying the responsible antibodies will be developed. The significance of "high-expression" of A/B antigens on platelets in NATP and other aspects or transfusion medicine will be defined. Molecular properties of the HNA-3a (5b) neutrophil antigen, an important trigger for transfusion-related acute lung injury (TRALI) will be determined. Drug-induced immune thrombocytopenia (DITP) (non-heparin). Mechanisms by which drugs induce drug-dependent antibodies (DDAbs) and promote binding of DDAbs to their targets will be characterized at the molecular level using both human DDAbs and murine monoclonal DDAbs that mimic their human counterparts. A unique NOD/scid mouse model will be used to define mechanisms of in vivo destruction of human platelets by human and murine DDAbs and to characterize drug metabolites capable of triggering DITP. A murine model of DITP will be explored. Improved methods for identifying agents responsible for immune cytopenia in individual patients will be developed. Heparin-induced thrombocytopenia (HIT). HIT is an important cause of morbidity and mortality in patients treated with this otherwise useful anticoagulant. We propose to address important unresolved questions concerning performance of diagnostic testing and interpretation of test results to improve diagnosis and management. Immune-mediated blood disorders and other types of drug sensitivity are a major cause of morbidity and mortality. The proposed studies will lead to a better understanding of causation and improved diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Immune-mediated thrombocytopenias and other blood disorders are a major cause of morbidity and mortality. The proposed studies will lead to a better understanding of causation and to improved diagnosis and treatment.